The alpha-chain of the T cell receptor (TCR) is intimately involved in recognition of antigenic peptide plus major histocompatibility complex (MHC) proteins. Investigation of the expression of a number of Valpha- regions using antibodies has shown, in both human and murine systems, that each Valpha is expressed mainly in either the CD4+ or CD8+ peripheral T cell subset. This is due to positive selection in the thymus. Recent data suggest that the Valpha-region of the TCR is also involved in recognition of superantigens. The major aim of this project is to identify the mechanisms controlling selection of Valpha into CD4 or CD8 peripheral T cell subsets and the means by which Valpha is involved in recognition events. Polymorphisms have been linked to multiple sclerosis and myasthenia gravis, indicating that it is important to determine the consequences of V alpha polymorphism on the immune repertoire. A polymorphism substituting a single amino acid in a Vbeta- region drastically alters TCR repertoire in mice. The predicted structure of the TCR suggest that the first complementarity determining regions (CDR) of the V-regions are involved in contact with the MHC, whereas the third CDR (encoded by the junction formed during gene rearrangement between the V-(D)-J elements) contact the antigenic peptide bound to MHC. The finding of skewed expression of Valpha in the CD4 (MHC class II-restricted) or CD8 (class I-restricted) subset, and the finding that two Valphas differing mainly in CDR1 and 2 have different superantigen-reactivities, suggests that he Valpha-region plays a major role in determining the MHC class recognized as well as in superantigen recognition. The question of whether the Valpha involvement in superantigen-recognition is active or a passive result of selection into the CD4 subset will be addressed. The region of the Valpha involved in superantigen recognition and/or MHC selection will be determined by transfection of mutated genes and by transgenic mice.